The direct and indirect health care costs associated with pulmonary arterial hypertension among commercially insured patients in the United States

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, progressive, and fatal disease associated with considerable overall clinical and economic burden. Although the direct health care costs of PAH have been well described, there are few data regarding indirect costs and productivity loss associated with PAH. Patient data were assessed until the earliest of death, end of full-time employment, end of continuous enrollment, or end of study period. OBJECTIVES: To update data on the direct burden and address the knowledge gap regarding the indirect burden associated with PAH. METHODS: This is a retrospective case-control study with prevalent and incident patients with PAH aged 18-64 years identified from the MarketScan Commercial and Health and Productivity management datasets during the identification period (January 1, 2016, to November 30, 2018). Patients were required to have continuous enrollment for 12 months or longer from the baseline period and 1 month or longer from the follow-up (post-index) period. Among patients with PAH (cases), the first observed PAH diagnosis claim date during the identification period was the index date. Patients without PAH (controls) were selected and assigned a random index date during the same period. Controls were matched 1:1 by age, sex, and region to prevalent and incident PAH cases. Per patient per month (PPPM), all-cause health care resource utilization, costs, and short-term disability (STD) were examined for cases and controls during the follow-up period. Multivariable analysis was performed using the generalized linear model to determine the adjusted direct and indirect health care utilization and costs. RESULTS: A total of 1,293 prevalent and 455 incident patients with PAH were identified. During the follow-up period, prevalent patients with PAH had significantly higher total mean all-cause health care costs ($9,915 vs $359, P < 0.0001) and inpatient length of stay (0.63 vs 0.02 days, P < 0.0001) PPPM as compared with controls. Prevalent patients with PAH had significantly longer STD (6.0 vs 1.5 days, P < 0.0001) and higher STD-related costs ($1,226 vs $277, P < 0.0001) PPPM as compared with controls. Incident patients with PAH had significantly higher total mean all-cause health care costs ($9,353 vs $336, P < 0.0001) and inpatient length of stay (0.92 vs 0.01 days, P < 0.0001) PPPM as compared with controls. Incident patients with PAH also had longer STD (8.1 vs 1.5 days, P < 0.0001) and higher STD-related costs ($1,706 vs $263, P < 0.0001), as compared with controls. CONCLUSIONS: This study showed that incident and prevalent patients with PAH had significantly higher direct and indirect health care resource utilization and costs as well as productivity loss compared with patients without PAH.


Plain language summary
Pulmonary arterial hypertension (PAH) is a progressive disease that is rare and fatal. The study aim was to update data on the direct burden (costs and utilizations for patients and payers) and address the knowledge gap regarding the indirect burden (eg, lost wages, lost productivity) associated with PAH. Results indicated high comorbidity and direct and indirect health care resource utilization and costs among the incident and prevalent PAH populations and among all the incident patients and those in the 55-64 years age group exhibiting the greatest burden.

Implications for managed care pharmacy
The economic burden of PAH may be underestimated because many elements such as lost wages and productivity are not included in cost estimates. PAH has a significant impact on not only health care resource utilization but also the earning prospects of those with this rapidly progressive disease. There is a need for ongoing work on the development and implementation of treatment strategies and/or interventions to improve the health outcomes for patients with PAH.
Pulmonary arterial hypertension (PAH) is a largely idiopathic, incurable, and debilitating disease that leads to right ventricular failure and premature death. 1,2 PAH is more common in women and in individuals aged between 30 and 60 years. 3 The European Society of Cardiology recommends 5 classes of drugs that have been approved for the treatment of PAH, including endothelin 1 receptor antagonists (ERAs; bosentan, ambrisentan, and macitentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), soluble guanylate cyclase stimulators, prostacyclin analogues, and prostacyclin IP receptor agonists (selexipag). 1 Although rare, PAH is responsible for considerable morbidity and economic burden and can seriously affect quality of life. [4][5][6][7] Misdiagnosis due to nonspecific symptomology and multimorbidity is common and overlooked, and occult cases often progress to later stages. 8,9 More than 70% of patients with PAH are diagnosed at advanced World Health Organization (WHO) functional classes (FCs) and are therefore more likely to be hospitalized. 10, 11 Overall, patients with PAH are at high risk of hospitalization and readmission. [12][13][14][15] Hospitalizations, especially readmissions, drive high direct health care costs among patients with PAH. [15][16][17] A 2015 observational study of pulmonary hypertension (PH)-related hospitalization reported annual mean costs of $42,455 for hospitalization with an average length of stay of 10.2 days. 15 Although wide variation between WHO FCs complicates definitive per-patient quantification, US costs have been estimated to range from more than $2,000 to more than $9,000 per patient per month (PPPM; 2014 US dollar). 15,18 Although the prevalence of misdiagnosis and underdiagnosis suggest actual costs may be underestimated, the generally high direct health care costs of PAH are well described in the real-world literature. 19,20 However, indirect costs remain understudied. 5,21 There is some survey-based evidence regarding the contribution of PAH-related lost work productivity to the indirect economic burden of the disease; an estimated 85% of patients with PAH have reported employment affected by PAH, and between 45% and 71% are unable to work at all for extended periods or permanently. [22][23][24][25] As the economic impact of PAH belies its relative rarity, understanding the incremental impact of associated indirect costs is important as it can inform overall burden and cost-effectiveness evaluations of treatment options, as well as economic projections for a range of stakeholders. Thus, to expand upon previous studies on health care costs and address the evidence gap regarding the costs associated with lost productivity, the authors undertook this retrospective case-control cohort analysis to examine patient characteristics and economic outcomes among incident and prevalent patients with PAH as compared with those without the disease. The study leverages linked data from a large commercial claims and health and productivity database to provide more comprehensive insight into the current economic burden of PAH in real clinical practice. The results can inform decision-making among health care administrators, payers, and policy makers.

STUDY DESIGN AND DATA SOURCES
This retrospective cohort study used the MarketScan Health and Productivity Management Database from January 1, 2015, to December 31, 2018. 26 This database contains integrated data regarding workplace absence, short-term disability (STD), and workers compensation for approximately 3 million employees. These deidentified data are linkable at the individual employee level to the medical, pharmacy, and enrollment data in other MarketScan commercial databases. 27 Raw data included comprehensive demographic, clinical, and treatment information identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes, National Drug Codes, and Common Procedure Coding System codes. The analyses did not involve the collection, use, or transmittal of individual identifiable data. Thus, institutional review board approval to conduct this study was not required.

CONCLUSIONS:
This study showed that incident and prevalent patients with PAH had significantly higher direct and indirect health care resource utilization and costs as well as productivity loss compared with patients without PAH.
To yield the final study sample, the case patients with PAH in both the prevalent and incident population were matched in a 1:1 ratio to their respective control patients by age, sex, and region. Patient data for the case and control cohorts were assessed until the earliest date of death, end of full-time employment, end of continuous enrollment, or end of study period.

BASELINE CHARACTERISTICS
Evaluated patient demographic characteristics as of the index date included sex, age, health insurance status, and geographic region. Clinical characteristics were evaluated from the 12-month baseline period through the index date and included Deyo-Charlson comorbidity index (CCI) scores 29,30 and individual comorbidities. Baseline all-cause health care utilization, costs, STD days, and indirect costs associated with STD during the abovementioned period were also evaluated.

STUDY OUTCOMES
Indirect health care costs and productivity loss outcomes were examined for patients with greater than or equal to 1 month of follow-up after enrollment during the follow-up period (main analysis) and for patients with a fixed 12-month follow-up period (sensitivity analysis). 31 Examined outcomes included STD days and associated indirect costs. STD was defined as employer-reported extended work absences of approximately 6 months, reported as PPPM. 28 Indirect health care costs were calculated by multiplying the number of days of lost productivity during the post-index period, based on the 2018 average daily wage rate for all occupations (assuming 8-hour workdays). diagnosis code for PH/PAH during the identification period. The first PH/PAH diagnosis claim date was defined as the index date. Patients were also required to have 1 or more claim for a PAH-specific medication (endothelin receptor antagonists, PDE5i, soluble guanylate cyclase stimulator, and prostacyclin pathway agents) on or any time after the index date. Continuous health plan enrollment and fulltime employment were required for greater than or equal to 12 months prior to the index date (baseline) through greater than or equal to 1 month post-index (follow-up) for all the patients included in the study. Patients were excluded from the case cohort if they had a claim of pregnancy, labor, delivery, or erectile dysfunction during the study period.
Case patients were stratified into incident and prevalent PAH populations. Incident patients with PAH were defined as patients with an index PAH/PH diagnosis claim but with no prior evidence of PAH/PH diagnosis during the baseline period. Prevalent patients with PAH were defined as any patient with an index PAH diagnosis claim with or without evidence of a prior PAH diagnosis claim during the baseline period. Incident and prevalent patients were not mutually exclusive. The patients with PAH/PH were defined using PAH/PH diagnosis claim and PAH medication claim or PAH/PH diagnosis claim with RHC procedure claim and PAH medication claim to capture most of the disease population. Control patients were aged 18-64 years without evidence of PAH at any time during the study period and assigned a random index date within the identification period. The control patients also had continuous health plan enrollment, and full-time employment in the 12-month baseline period and greater than or equal to 1-month follow-up period.  Direct health care resource utilization (HCRU) and costs were examined during the entire follow-up period for patients with greater than or equal to 1 month of follow-up (main analysis) and for the fixed 12-month follow-up period (sensitivity analysis). Direct HCRU and costs included allcause utilization and associated all-cause health care costs in various capturable settings. Costs were calculated PPPM and adjusted to 2018 US dollars using the medical care component of the Consumer Price Index. 18

STATISTICAL ANALYSIS
All variables were analyzed descriptively with means and SDs reported for continuous variables. Counts and percentages were reported for categorical variables. P values were calculated using chi-square tests for categorical variables and t-tests for continuous variables.
Generalized linear models assuming γ distribution with a log link function were used to compare the direct and indirect health care costs as well as HCRU and STD days between PAH cases and controls. Clinical characteristics (CCI scores, individual comorbidities) were adjusted in the models. Analyses were performed using SAS for Windows, Version 9.4 (SAS Institute Inc.).   (Table 3).

Discussion
This large, retrospective cohort study leveraged linked health and workplace data to evaluate the direct and indirect economic burden of working-aged commercial insurance enrollees with PAH as compared with those without PAH. The results add nuance to the evidence regarding the true economic impact of PAH, in particular the indirect costs of lost work productivity. We found that the patients with PAH in our sample were predominantly middle-aged men with multiple comorbid conditions. Although the

ADJUSTED HEALTH CARE COSTS AND UTILIZATION OUTCOMES
Prevalent Patients With PAH. The average length of followup was 587 days for the prevalent PAH cases vs 634 days for controls. HCRU was significantly higher among patients with PAH as compared with controls. Specifically, prevalent cases had more inpatient stays PPPM (0.07 vs 0.00 days; P < 0.001) and longer length of stay PPPM (0.63 vs 0.02 days; P < 0.001) as compared with controls (Table 1). Mean total all-cause health care costs were considerably higher for the prevalent cases as compared with controls ($9,915 vs $359; P < 0.001 PPPM) and were mainly driven by inpatient (46.6%) and pharmacy (28.0%) costs for prevalent cases (Figure 1). HCRU and cost trends were similar in sensitivity analyses (Table 1, Figure 1).  Figure 2).  cohorts were neither matched nor mutually exclusive, we noted numerically higher pharmacy and total HCRU and costs among prevalent cases but higher inpatient HCRU and costs among incident cases. Specifically, incident cases had more inpatient visits and longer inpatient stays as compared with prevalent cases, suggesting that newly diagnosed cases incur more HCRU. This finding aligns with observations of Gérald et al (2015), who reported higher hospitalization rates and increased disease progression among incident PAH cases as compared with prevalent cases. 33 These discrepancies underscore hospitalization as a major PAH cost driver. Given that PAH is underdiagnosed, and hospitalization is also associated with advanced FC and increased risk of negative outcomes, 9,15,18 our findings emphasize the importance of early detection and intervention to prevent hospitalization and readmission. Although novel, our results for indirect outcomes are also generally consistent with survey-based data suggesting a considerable burden of PAH on health-related quality of life, including the ability to work. [22][23][24][25] Similar retrospective studies on the indirect economic burden of chronic obstructive pulmonary disease (COPD) may also serve as general points of reference. 26,34 A 2014 systematic proportion of male patients was unusually high given PAH disproportionately affects women, 12,19 our findings likely reflect the predominance of males with linked Health and Productivity Management information in the database and in the workplace. 32 We observed that newly diagnosed and older patients with PAH had significantly higher direct and indirect health care costs as well as greater productivity losses, as compared with their counterparts without PAH. Consequently, it is worth considering that newly diagnosed patients and those in the 55-64 years age group may benefit from comprehensive support services and early introduction of combination therapy management per guidelines to maximize patient outcomes as early as possible in the disease process.

ADJUSTED PRODUCTIVITY LOSS AND INDIRECT COSTS OUTCOMES
Although differences in patient populations and methods preclude direct comparisons, our findings of $9,353 (incident) to $9,915 PPPM (prevalent; 2018 USD) for mean direct all-cause health care costs among all patients with PAH fall within the general range of $2,476 to $11,875 PPPM (2014 USD) reported in a 2016 literature review and a generally similar 2017 costs analysis. 5,18 Cost distributions between prevalent and incident cases in our study were also notable; although they were not statistically comparable, as the

FIGURE 2
Adjusted incurred by this patient population as well as strategies for earlier detection and intervention, clinician awareness of treatment guideline recommendations, and continued development of clinically and cost-effective treatment options. Early PAH diagnosis and prompt, appropriate treatment has the potential to lower direct and indirect spending. In addition, identifying patients most at risk for hospitalization may also help clinicians lower patient and payer costs.

STRENGTHS
Notable strengths of this study design include the large study sample with linked health and comprehensive workplace data, which captures a broad range of complications, providers, and economic outcomes that might not be observable prospectively. Moreover, the study presents novel results among an understudied patient population.

LIMITATIONS
The results should be interpreted within the context of certain limitations. As with all retrospective designs, the present study is limited to the observation of associations as opposed to inference of causality. Moreover, although claims data are extremely valuable to augment randomized controlled trial results with insight into real clinical practice, all claims databases have certain inherent limitations because the claims are collected for administrative purposes and not research and therefore may lack certain clinical information or include coding discrepancies. In this study specifically, such coding discrepancies may lead to underestimation of recent costs, especially among incident patients with PAH, as PAH is often attended by review of COPD studies reported that the annual mean perpatient indirect costs associated with COPD in the United States, including costs associated with mortality, ranged between $1,521 and $3,348 (2010 USD), 26 as compared with $1,230 (prevalent) to $1,718 (incident) in our study (excluding mortality; 2018 USD). In 2018, a similarly designed cohort analysis on a commercially insured population found 2 times higher incremental STD costs among (prevalent) patients with COPD vs controls, as compared with our findings of 4 times higher STD among prevalent cases vs controls. 34 Our data should be interpreted in the context of the likely underestimation of true indirect costs due to the unavailability of data in this dataset with which to evaluate lost work productivity among family caregivers and other family members as well as other incidental related expenses, such as increased transportation or other household expenses. 23,35 About 85% of patients with PAH had their employment affected in some way. Caregivers in particular may have their own quality of life, work performance, ability to work, and income affected, and this in turn can reduce household income. 23,27 International survey data from France, Germany, Italy, Spain, and the UK have reported that 43% of caregivers experience exhaustion, 29% had their ability to work affected, and 35% reported a major impact on income. 23 US PAH Association survey data have reported that 20% of caregivers stopped working altogether. 23 Regardless of the limits of data observable in claims, we found considerable disease burden associated with PAH, and on their own merits, the data clearly call for continued research into both the direct and indirect costs

Adjusted STD Days Loss and Cost for Prevalent and Incident PAH Cases and Controls
During the Follow-Up Period nonspecific symptomology and may be diagnosed late in progressionhence, costs related to PAH may in fact have been unobservable because of miscoding. Other study-specific limitations include actual pay rates of individuals, which might be different from the average hourly pay rates used for computing productivity loss costs, possibly leading to over-or underestimation. Although regression models were adjusted for comorbidities, there may be residual confounding in addition to the possibility of the abovementioned hidden costs of suboptimal treatment.
Another limitation is that the study may not be entirely representative of the severe PAH population. This is due to potential selection bias in the study, as healthier patients are mostly represented in a commercial insurance database when linked to employment database. Therefore, patients who are too sick to work are less likely to be on the linked commercial database in the first place. Finally, because some of the prevalent patients might have been categorized as incident owing to the baseline period of 12 months, the incidence might be overestimated.

Conclusions
Our large, retrospective cohort analysis leveraged linked health and workplace data to evaluate the direct and indirect economic impact of PAH. Our results revealed high comorbidity and direct and indirect HCRU and costs among the incident and prevalent PAH population, with incident patients and those aged 55-64 years exhibiting the greatest burden. As PAH imposes a significant burden on individual patients and their families, employers, and payers through both health care costs and lost productivity, these data improve our understanding of the overall societal impact of this debilitating and costly disease.